1. Field of the Invention
The present invention concerns treating patients suffering from psychomotor stimulant (cocaine, methylphenidate and the amphetamines) and other substance abuse or dependence disorders by administering a pharmaceutically active compound, which results in aversive symptoms when combined with the stimulant.
2. Background Information
One of the most problematic addictive habit disorders is "crack" cocaine molding. "Crack" cocaine smoking has now produced epidemic cocaine dependence in the urban United States, following earlier epidemic abuse in the Bahamas (Jekel, J. F., Allen, D. F., Podlewski, H. Clarke, N. Dean-Patterson, S. Cartwright, P., "Epidemic Cocaine Free-Base Abuse: Case Study from the Bahamas," Lancet. (1986), 1, 459, 462).
Cocaine, the amphetamines, and methylphenidate are equivalent in their central effects, in their abuse liability, and in the treatments employed to combat their abuse (Gawin, F. H., Ellinwood, E. H., "Cocaine and Other Stimulants; Actions, Abuse, and Treatment," New Engl. J. Med (1988), 318, 1173-1182 and Gawin, F. H., Kleber, H. D., "Evolving Conceptualizations of Cocaine Dependence," Yale J. Biol. Med., (1988) 123-136). Smoking is the most common administration route in severe dependence and abuse, but intravenous, intranasal, oral and other administration routes can all produce abuse and dependence requiring treatment.
"Crack" is defined as cocaine distributed in ready-to-smoke form (cocaine free-base), rather than as the injectable or insufflatable cocaine hydrochloride. Previously, cocaine smoking ("freebasing") required a complex extraction by the end user, of free cocaine base from cocaine hydrochloride, limiting the availability and thus the extent of cocaine dependence by smoking (Gawin and Ellinwood, supra).
"Crack" is generally sold in small, inexpensive one or two inhalation quantities, in a marketing system that, in contrast to prior cocaine distribution, saturates a region with ubiquitous "street" cocaine distributors. The combination of low initial expense, unprecedented availability, and extreme abuse liability has resulted in an epidemic of refractory, recurrent cocaine dependence, making obvious the limits of current cocaine abuse treatment strategies for "crack" abuse, and has lead to unprecedented levels of public concern. Recently, similar epidemic methamphetamine use patterns have also appeared, as has methamphetamine smoking ("crank" or "ice").
Stimulant abstinence is characterized by days to months of dysphoria (Gawin, F. H., Kleber, H. D., "Abstinence Symptomatology and Psychiatric Diagnosis in Chronic Cocaine Abusers," Arch. Gen. Psychiatry (1986), 43, 107-113) that produces craving. Episodically and indefinitely thereafter additional pulsatile craving is produced by unpredictable exposures to cues that evoke vivid memories of drug euphoria.
Prior outpatient pharmacotherapy trials for cocaine dependence demonstrate that heterocyclic antidepressants are sometimes effective in enhancing initial attainment of cocaine abstinence, but that their efficacy, as in treatment of depression, is delayed by 10-14 days from the outset of therapy (Giannini, A. J., Malone, D. A., Giannini, M. C., Price, W. A., Louiselle, R. H., "Treatment of Depression in Chronic Cocaine and Phencyclidine Abuse with Desipramine," J. Clin. Pharmacol. (1986), 26, 211-4 and Gawin, F. H., Kleber, H. D., Byck, R. Rounsaville, B. Kosten, T. R., Jarlow, P., Morgan, C. "Desipramine Facilitation of Initial Cocaine Abstinence," Arch. Gen. Psychiatry (1989) Arch. Gen Psychiatry, 46, 117-121). Further, efficacy is not prolonged beyond six weeks of treatment, so only an effect facilitating initial abstinence and none on long-term relapse prevention exists (Carroll, K. M. Rounsaville, B. J., Gordon, L. T., Jatlow, P. M., Nich, C., Bisighini, R. M., and Gawin, F. H., "Psychotherapy and Pharmacotherapy for Ambulatory Cocaine Abusers," Arch. Gen. Psychiatry (1994), 51, 177-87). In outpatient "crack" smokers, the extreme availability of the drug often results in resumption of cocaine smoking early in treatment, producing non-compliance to voluntary oral medication regimens that usually results in cessation of all forms of treatment, including psychotherapy, before the possible onset of any therapeutic medication effects (Gawin, Kieber, Byck, Rounsaville, Kosten, Jatlow and Morgan, supra). In this context, 1) a depot long acting preparation would have advantages over other methods of medication administration; 2) more rapidly acting agents are needed and unavailable; and 3) no long term relapse prevention agent exists.
Flupenthixol decanoate is a long acting depot xanthene derivative with unique properties, having both delayed antidepressant activity at low doses (Poldiger, W. Siebems, S., "Depression-inducing and Antidepressive Effects of Neuroleptics: Experiences with Flupenthixol and Flupenthixol Decanoate," Neuropsychobiology (1983), 10, 131-136 and Robertson, M. M., Trimble, M. R. (1982), "Major Tranquilizers Used as Antidepressants," J. Affective Dis. 4, 173-195) and immediate neuroleptic activity at higher doses (Trueman, H. R., Valentine, M. G. (1974) "Flupenthixol Decanoate In Schizophrenia," Br. J. Psychiatry, 124, 58-59).
Similar to tricyclic antidepressants, it was thought depot flupenthixol decanoate both might positively influence the outcome of the treatment of the habit disorders and obviate compliance problems. However, double-blind studies demonstrating that flupenthixol decanoate significantly improves mood, craving or cocaine use over placebo have not been reported.
Another clinical approach to addictive therapy is the pharmacological production of symptoms of aversion to the agent causing the addiction. This is the basis for disulfiram (antabuse) treatment of alcoholism, which has demonstrated clear rapidly acting efficacy both as an abstinence initiation facilitating treatment and relapse prevention treatment, but predominantly in motivated sub-populations whose use is strongly linked to unpredictable cues. In such cases the craving based on the expectation of stimulant euphoria is reduced or eliminated because aversive symptoms are expected. However, to date, no safe, aversive pharmacological method for psychomotor stimulant (cocaine, the amphetamines or methylphenidate) abuse and dependence that parallels the use of disulfiram ("antabuse") for alcohol abuse has yet appeared. A new, aversive pharmacological interaction between neuroleptics and psychomotor stimulants that leads to therapeutic improvement of stimulant abuse and dependence has been needed.
It is therefore a principal object of the present invention to reduce or eliminate stimulant abuse and dependence in actively using humans, or in patients who have established abstinence of several weeks, to help prevent relapse indefinitely.